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Tungstate-Targeting of BKαβ(1) Channels Tunes ERK Phosphorylation and Cell Proliferation in Human Vascular Smooth Muscle
Despite the substantial knowledge on the antidiabetic, antiobesity and antihypertensive actions of tungstate, information on its primary target/s is scarce. Tungstate activates both the ERK1/2 pathway and the vascular voltage- and Ca(2+)-dependent large-conductance BKαβ(1) potassium channel, which m...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320054/ https://www.ncbi.nlm.nih.gov/pubmed/25659150 http://dx.doi.org/10.1371/journal.pone.0118148 |
Sumario: | Despite the substantial knowledge on the antidiabetic, antiobesity and antihypertensive actions of tungstate, information on its primary target/s is scarce. Tungstate activates both the ERK1/2 pathway and the vascular voltage- and Ca(2+)-dependent large-conductance BKαβ(1) potassium channel, which modulates vascular smooth muscle cell (VSMC) proliferation and function, respectively. Here, we have assessed the possible involvement of BKαβ(1) channels in the tungstate-induced ERK phosphorylation and its relevance for VSMC proliferation. Western blot analysis in HEK cell lines showed that expression of vascular BKαβ(1) channels potentiates the tungstate-induced ERK1/2 phosphorylation in a G(i/o) protein-dependent manner. Tungstate activated BKαβ(1) channels upstream of G proteins as channel activation was not altered by the inhibition of G proteins with GDPβS or pertussis toxin. Moreover, analysis of G(i/o) protein activation measuring the FRET among heterologously expressed G(i) protein subunits suggested that tungstate-targeting of BKαβ(1) channels promotes G protein activation. Single channel recordings on VSMCs from wild-type and β(1)-knockout mice indicated that the presence of the regulatory β(1) subunit was essential for the tungstate-mediated activation of BK channels in VSMCs. Moreover, the specific BK channel blocker iberiotoxin lowered tungstate-induced ERK phosphorylation by 55% and partially reverted (by 51%) the tungstate-produced reduction of platelet-derived growth factor (PDGF)-induced proliferation in human VSMCs. Our observations indicate that tungstate-targeting of BKαβ(1) channels promotes activation of PTX-sensitive G(i) proteins to enhance the tungstate-induced phosphorylation of ERK, and inhibits PDGF-stimulated cell proliferation in human vascular smooth muscle. |
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